Purpose This paper examines the early pandemic experience in a large metropolitan area to differentiate the roles of the lifestyle and built environment factors associated with differing case rates across neighborhoods. Design/methodology/approach This paper develops a simple empirical methodology for sorting out the separate effects of lifestyle and the built environment factors along with their interactive effects when individuals’ behaviors not only reflect their observable characteristics but also are influenced by the physical environments in which they live and work, indirect connections implied by the early insights of Jacobs (1961) and more recently Hawley and Turnbull (2019). Findings The results demonstrate that lifestyle factors tied to employment show the strongest association with COVID-19 cases. Other lifestyle choices, built environment features, and demographic attributes such as household size, principal cities, highway connectivity, and population density also affect COVID-19 transmission at the onset of the disease outbreak. The analysis reveals a surprising spatial pattern; employment-related lifestyle factors on case rates in outlying neighborhoods are stronger than in neighborhoods within primary cities after accounting for various built environment factors. Originality/value This research addresses important questions and the perplexing outcomes related to lifestyle and the built environment’s multi-faceted role in spreading COVID-19. In addition, this study represents a pioneering effort in disentangling the pure lifestyle effect on virus transmission after eliminating potentially confounding impacts of built environment factors on household behavior that in turn influence virus transmission.